New quaternary compounds having anti-microbial activity

ABSTRACT

Novel quaternary ammonium compounds which include the adamantane ring system linked to the quaternary ammonium group by a hydrocarbon chain or by other functional groups, such as ether, carboxylic ester, carboxamide, keto, carbamate ester, thiocarbamate ester, etc.

United States Patent [191 Bauman Dec. 23, 1975 NEW QUATERNARY COMPOUNDS [58] Field of Search 260/468 G HAVING ANTI-MICROBIAL ACTIVITY 75 Inventor: Robert Andrew Bauman, New I References Cited Brunswick, UNITED STATES PATENTS [73] Assignee: Colgate-Palmolive Company, New 3,565,942 2/1971 Krimmel 260/468 York, N.Y. 22 Filed: Sept 24 973 Primary Examiner-Robert Gerstl Attorney, Agent, or FzrmRobert L. Stone; Herbert S. pp Ne1400,097 Sylvester; Murray M. Grill Related U.S. Application Data [63] Continuation of Ser. No. 39,536, May 21, 1970, [57] ABSTRACT abandmed- Novel quaternary ammonium compounds which include the adamantane ring system linked to the qua- [52] U.S. Cl...... 260/468 G; 260/455 A; 260/468 E; ternary ammonium group by a hydrocarbon chain or 260/557 B; 260/567.6 M; 424/300; 424/305; by other functional groups, such as ether, carboxylic 424/320; 424/324 ester, carboxamide, keto, carbamate ester, thiocarba- [51] Int. Cl. C07C 93/04; C07C 93/ 197; mate ester, em

C07C 103/737; C07C 87/30 4 Claims, N0 Drawings NEW UATERNARY COMPOUNDS HAVING ANTI-MICROBIAL ACTIVITY This is a continuation, of application Ser. No. 39,536

2 2-( 1-adamantylthiocarbamyloxy)ethyldimethyldodecylammonium bromide. The halides such the chlorides, fluorides and analagous compounds may also be employed herein as effecfiled May 21, 1970 now abandoned. 5 tive anti-bactericides. V

The present invention relates to novel quaternary It has been observed that the compounds generally ammonium compounds represented by the general described by the foregoing formula are particularly formula: effective against gram positive organisms such as H- Ni (CHMZRII X 1 I Staphylococcus aureus Streptococcus mitis, Bacillus wherem R l'adamantyl (CWHIE), R a long Cham subtilis, Corynebacteriu'm acnes, and against fungi, such alkyl group of carbon atoms Z Selected from as Candida olbicans, Triclzoplzyton mentogrop/zyles and the group conblstmg of [Cl-I2 CONH Axpergillus niger, and moderately effective against Esand Fb l 'L 1%: mtegertfmm I ceric/zia coli which is a gram negative bacteria. Com- 0 an a compa e amonese qua emary pounds wherein R is a benzyl radical in lieu of instant compotfnds PosslesS f P annmcroblal higher alkyl radical are devoid of antibacterial activity. gh 'g 'g I d d f t The anti-microbial nature of the instant novel come a aman y ra Ica 1s er1ve rom r1cyclo[3 3 l l 7] decane showin four trans c clohexane p-ounds (as by d Stdnqdrd test tube send] dllu g t1on test In which an approprlate number of test tubes rmgs as follows: of broth containing decreasing concentrations of the test agent was inoculated with the test organism. After a suitable period of incubation the tubes were examined for the presence or absence'of growth. The activity of the test agent was the lowest concentration which inhibited the growth of the organism and is expressed as the minimal inhibitory concentration in #g/ml. TABLE 1 Minimum Inhibitory Concentration (pg/ml) R Z R n S.aurcus S.mitis B.suhtilis C.acncs C.alhicans T.mentagrophytcs A.niger E. coli Adamantyl- COO c...|-1 2 1.56 6.25 1.56 1.56 12.5 7.1: 31.2 25 Adamantyl coo C.2H 2 .02. .19 .19 6.25 .711 6.25 1 511 12.5 Adamantyl COO CHH-w 2 .78 .78 .l 25. 6.25 25 50 51) Adaman'tyl CONH C m, 3 .78 .39 6.25 12.5 25 50 Adzlmantyl (.ONH uHzn 3 .39 .39 6.25 25 50 Adumantyl 0 0. 11 2 .39 .19 1.56 3.12 50 12.5 Adamantyl O CH M] 2 .78 .3) L56 6.25 50 12.5 Adamantyl NHCSO C,- ,H2 2 1.56 .78 .39 12.5 6.25 3.9 62.5 25

H 2 C These d1lution tests evidence the effectiveness of lo 40 compounds of the invention against bacteria and fungi. Hc c H When used against bacteria or fungi, compounds of the instant invention may be applied directly to the 7 H 3 surface to be protected or may be dissolved in a pharc I maceutical carrier. Typically, an effective amount, e.g. 8 2 0.1 to about 10% by weight of the compound, is included in an inert carrier and a dispersing or surface active agent. Alternatively, an effective amount, eg 2 c 6 9 2 4 CH 0.1 to about 10% by weight may be incorporated into a I 2 solid carrier which may be inert, such as talc, clay, 5 diatomaceous earth, flour, etc.

g c The quaternary ammonium amides of adamantyl H carboxylic acid are particularly effective in inhibiting Typical examples of the quaternary ammonium Com the development of dental calculus as shown by the Pounds which may be used in this invention results of tests on lltter-mated albmo rats, In groups of 2-( l -adamantanecarbonyloxy)ethyldimethyldecy- 15 males and 15 families t were fed a Z'pkm' Clammoniumbmmide McClure calculus producmg mm. For 6 weeks the teeth l tadamamanecarbowloxy)ethyldimethyltet I of each ammal were swabbed for 30 seconds each day radecylammonium bromide w1th a test solut1on or water for the control group. The 3 (1l adamanmnecarboxamido)propy1dimethy| aBmmals were then safnficed, defleshed and scored by dodecylammonium bromide baesr sdmethod for ca culus. The results were analyzed 3-( l 'adamantanecarboxamido)propyldimethyltetem 5 t test and m the results quoted were 99% radecylammonium bromide, l-adamantyloxyethyldimethyltetradecylammonium bromide C d C Cll1'Rd"'/ l-adamantyloxyethyldImethyldOdecyIammomum "mwun fif bromide 3- 1'-- d I '7 2. 3 6.27 l-adamantylcarbonylmethyldImethyltetradecylami i i zfis I 4 4 monium bromide gr pfi t y l-adamantylcarbonylmethyldimethyldodecylammonium bromide The results set forth above indicate the significant effectiveness of the quaternary compounds of the invention in inhibiting formation of oral calculus in concentrations as low as 0.1%. 5 EXAMPLE I When compounds of the instant invention are in- Dental-Cream c tended for use in compositions which reduce formation f I d h-b-t f tf l I l I Quaternary ammonium ester q a m 1 l i lon 0 0rd y f of adamantyl carboxyllc acld 0.50 typically incorporated in oral preparation In effectlve gp g v yccrme -s. l amounts up to about 5% by weight, preferably 0.l-1% Sodium pymphosphmc (L25 and most preferably 0.25-0.5% by weight of the oral Carboxymcthyl cellulose 0.85 preparation. Typically, the oral preparation is a dentrifrice, such as a dental cream, tablet or powder, contain- Calcium carbonate (precipitated) 5:00 ing as a vehicle about -95% by weight of a water- Qi f phvsllhflw dihydww 8-; insoluble polishing material, preferably including wal5 23:15 ter-insoluble phosphate such as dicalcium phosphate,

Iwccn 8O l)l \'UX \Clh \'lLllt: 910 moles ethylene oxltlcl sorbllan monooleale. trlcalcium phosphate, trlmagneslum phosphate. The dentrifrice may also include water; binders such as glycerine, sorbitol, propylene glycol, and polyethylene EXAMPLE 2 glycol 400, detergents, gelling agents such as Irish moss 20 M Outhwflsh and sodium carboxymethyl cellulose; additional anti- 7! bacterial agents; coloring or whitening agents; preser- Quaternary amminium amide ofadamantyl carboxylic acid 0.25 Vdt1V6b, slllcones, chlorophyll compounds, add1t1onal Nunionic detergent (plumnic R68), L00 ammonlated materials; flavoring or sweetening materl- Ethyl alcohol (containing flavor) l5.00 als; and compounds which provide fluorine-containing 25 Saccharln 0.02 ion such as sodium fluoride, stannous flourlde and Water 73,73 sodium monofluorophosphate. *3] k I [80/ I h I a u a "1 l ,Ihe a C pt ymbl' 0 p0 yOXytl )LFIL and 07 POUOXyPI'OIQILI'IL, mouth rinse which typically contains 2099% by weight of an aqueous alcohol such as ethanol, n-propyl, or The quaternary ammonium esters of adamantane isopropyl alcohol and being present in amount of about carboxylic acid can be prepared by a two-step process 53()% by weight of the oral preparation. of reacting adamantanecarboxylic acid chloride with a Such oral preparations are typically applied by brushdimethylaminoethanol to form the carboxylate, foling the teeth or rinsing the oral cavity for 30-90 seclowed by quaternizing with an alkyl halide as illustrated onds at least once daily. Typical oral preparations of by the following equations:

l COCl l C H c 2 I c H 2 C H I 2 ,C H

HOCH CH N 3 c c H H H c H 3 HC 2 \CH the invention which'can be applied in this manner are set forth below. I

2c l cu CH/H CH HCl C00CH2CH2N(CH3 c 12025 The quaternary ammonium amides of adamantanecarboxylic acid can also be prepared by a two-step method of reacting the adamantanecarboxylic acid chloride with a dimethyl diamine and subsequently quaternizing with an alkyl halide.

- Similarly, the quaternary ammonium compounds of this invention, represented by the following formulae:

IRO((H ),,N*(CH .RIX [RCO(C gl :|)2 l IRNHCSOICH:),,N*(C'H;|)2R'IX |RSt('H:),,N'(CH;,)=RlX IRNHCOO(CH:),,N*(CH,,):R'IX [RCH0H(CH. ,J,,N(CH;,)2R']X [R("H:(CH2),,N+(CH3):RIX wherein R, R. n and X have the same designations as in the general formula, can also be prepared by a simi lar two-step method of reacting a compound containing the adamantane radical with a compound containing the dimethyl amine radical and then quaternizing with a higher aliphatic halide.

The following examples illustrate the manner in which compounds of this invention are prepared.

EXAMPLE 3 Preparation of 2-( 1'-adamantanecarbonyloxy)ethyldimethyldodecylammonium bromide:

A solution of 21.7g (0.11 mole) l-adamantanecarboxylic acid chloride in 100 ml. ether was added to a solution of 19.4g. (0.22 mole) 2-dimethylaminoethanol in 200 ml. ether. The reaction mixture was stirred overnight at room temperature. Since unreacted acid chloride could still be detected by infrared spectrum, additional 15 g. (0.17 mole) 2-dimethylaminoethanol was added and the reaction mixture again stirred overnight. The reaction mixture was poured into 300 ml. water and treated with 20 ml. of 10% NaOH solution. From the ether layer was recovered 23g. of oil with an infrared spectrum compatible with the proposed structure Analysis: Found Calculated Carbon 64.95 64.78 Hydrogen 10.15 10.07

EXAMPLE 4 The decyl homolog of the above carboxylate, i.e., where R is H was prepared similarly to Example 3. The recovered erystals'had a melting point of 183l84.5C and the following analysis:

Found Calculated Carbon 63.00 63.54 Hydrogen 9.90 9.81

EXAMPLE The tetradecyl homolog was prepared in accordance with the process defined in Example 3, yielding crystals having a melting point of 176 178C with the following analysis:

Preparation of 3-(1'-adamantanecarboxamido)- propyldodecyldimethylammonium bromide: 2.5 grams of N,N-dimethyl-l,3-propane diamine was added to a cold solution of 5 grams l-adamantane carboxylic acid chloride in cc benzene. An immediate precipitate formed. The mixture was stirred and permitted to sit for minutes. The precipitate was washed with benzene several times, centrifuged, and dried in vacuum, yielding 5 grams of N-(3-dimethylaminopropyl) adamantane l-carboxamide hydrochloride having a melting point of l54l57C. This product was dissolved in 150cc acetone, placed in a refrigerator for crystal growth and 4.8 gms of the product was recovered.

This hydrochloride was dissolved in cc water and 25cc of 1N NaOH was added. A white precipitate formed which was extracted with ether, dried by flash evaporation and 3.2 grams of the free base having a melting point of 7880C was recovered. The infrared spectrum continued the structure of this product.

The aforedefined reaction product was quaternized by reacting 1.6 grams (0.06 mole) of N-(3-dimethylaminopropyl 1 -adamantanecarboxamide with l .5 grams (0.06 mole) of l-bromododecane dissolved in 4cc acetone. After standing for 2 weeks the reaction mixture was chilled with dry ice. The resultant crystalline mass was washed with ether, dried in vacuum and recrystallized from ethyl acetate, giving a crystalline product having a melting point of l22l24C and the following analysis:

The tetradecyl homolog of the above carboxyamide was prepared in accordance with the process of Example 6. The recovered crystals had a melting point of l22C and the following analysis:

Found Calculated Carbon 65.80 66.52 Hydrogen 10.54 10.61 Molecular weight 541.71

EXAMPLE 8 Preparation of l-adamantyloxyethyldimethyltetradecylammonium bromide:

A mixture of 3.6g (0.015 mole) 1-(2-dimethylaminoethoxy) adamantane [prepared by the method of Charkrabarti, Faulis and Szinai, Tetrahedron Letters, No. 60, 6249 (1968)] and 4.3g (0.05 mole) l-bromotetradecane was prepared and allowed to stand at room temprature for 6 days. The resultant solid was recrystallized from 30cc ethyl acetate to 4.75g white crystals. After recrystallization it melted at 132135.

Found Calculated Carbon 67.32 67.17 Hydrogen 10.96 10.87 Bromine 15.92 15.96

EXAMPLE 9 The dodecyl homolog was prepared by the procedure of Example 8, yielding hygroscopic crystals having a melting point point when dry of l28l30 and the following analysis:

Preparation of 1-adamantylcarbonylmethyldimethyltetradecylammonium bromide.

A mixture of 1.3g. (0.005 mole) l-adamantyl bromomethyl ketone and 1.23g (0.005 mole) dimethyltet-' radecylamine was solubilized by the addition of 30cc acetone. The next day the solidified mixture was washed with ether and recrystallized from ethyl acetate to yield 2.1g white crystals, m.p. l34-135.5.

Found Calculated Carbon 67.72 67.45 Hydrogen 10.65 10.51

EXAMPLE 1 1 The dodecyl homolog was prepared by the procedure of Example 10 yielding white crystals of melting point 141.5 and with the following analysis.

Found Calculated Carbon 66.55 66.36 Hydrogen 9.87 10.28

9 EXAMPLE 12 2-( 1'-adamantylthiocarbamyloxy)ethyldimethyldodecylammonium bromide was prepared by a twostep process. First, l-adamantyl isothiocyanate was reacted with the sodium derivative of 2-dimethylaminoethanol. The product after recrystallization from ethylacetate and from hexane had a melting point of 8688.5 and an analysis of Found Calculated Carbon (14.02 63.79 Hydrogen 9.4l 9.28

A solution of 4.5g of the above-prepared O-(2-dimethylaminoethyl) l-adamantylthiocarbamate and 4.0g l-bromododecane in cc acetone was allowed to stand for 4 days. The product was recrystallized from ethylacetate and from acetone in white crystals, m.p. 143143.5 and had the following analysis Found Calculated Carbon 6!.(14 (10.99 Hydrogen 9.65 9.67

Although this invention has been described with reference to specific examples, it will be apparent to one skilled in the art that various modifications may be made thereto which fall within its scope.

What is claimed is:

l. A chemical compound having the structural forethyldimethyltetradecylammonium bromide. 

1. A CHEMICAL COMPOUND GAVING THE STRUCTURAL FORMULA
 2. A chemical compound as set forth in claim 1, wherein n is two.
 3. A chemical compound as set forth in claim 2, having the formula 2-(1''-adamantanecarbonyloxy) ethyldimethyldodecylammonium bromide.
 4. A chemical compound as set forth in claim 2, having the formula 2-(1''-adamantanecarbonyloxy) ethyldimethyltetradecylammonium bromide. 